The big four in the pathogenesis and pathophysiology of prurigo nodularis: Interplay among type 2 inflammation, epidermal hyperplasia, dermal fibrosis, and itch from neuroimmune dysregulation

Abstract

Prurigo nodularis (PN) is a distinct inflammatory dermatosis. It is characterized by intensely pruritic, firm nodules, typically 1 to 2 cm in diameter, which usually develop on the extensor surfaces of the extremities. Histopathologically, the following characteristics are observed in PN lesions: (1) dermal cellular infiltrates composed of type 2 inflammation-associated immune cells with lesional overexpression of type 2 cytokines (including interleukin [IL]-4, IL-13, and IL-31), (2) dermal fibrosis, and (3) epidermal hyperplasia with hyperkeratosis. Additionally, functional and structural alterations of cutaneous sensory nerve fibers profoundly contribute to itch in cooperation with type 2 inflammation. This abnormal interaction is referred to as neuroimmune dysregulation. The scratching behavior induced by itching from neuroimmune dysregulation initiates the development of prurigo nodules. This distinctive pathogenic feature of “itch-first” in PN is distinct from “inflammation-first” in atopic dermatitis, where the skin initially exhibits type 2 inflammation, which is subsequently followed by itching. The interplay between the four elements, namely type 2 inflammation, epidermal hyperplasia, dermal fibrosis, and itch resulting from neuroimmune dysregulation, appears to be pivotal in the pathogenesis and pathophysiology of PN.